Assignment on Nano drug delivery

Course code: PHRM 402 Course name: Pharmaceutical Technology II Section: 2

Submitted to: Dr. Repon Kumar Saha Assistant Professor

Submitted by: Sharmin Sheikh (ID: 2010-3-70-007) Trisha Debnath (ID: 2010-3-70-015) Nabeela Zaman (ID: 2010-3-70-043) Samiya Khondaker Rinta (ID: 2010-3-70-048)

Department of Pharmacy East West University

18th May, 2013

CONTENT
PAGE No.

Introduction Nano drug delivery Nanocarriers of drug delivery system Recent discoveries Some applications of Nano drug delivery and their mechanisms Advantages of nano drug delivery Nano drug technology in Bangladesh Challenges of Nanotechnology for Drug Delivery Conclusion Reference

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Introduction
At present 95% of all new potential therapeutics have poor pharmacokinetics and biopharmaceutical properties. Therefore, there is a need to develop suitable drug delivery systems that distribute the therapeutically active drug molecule only to the site of action, without affecting healthy organs and tissues. Nanotechnology plays an important role in therapies by lowering doses required for efficiency as well as increasing the therapeutic indices and safety profiles of newer therapeutics. In particular, nano-scaled carriers have revolutionized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. Implementation of nanotechnology in medicine means that mechanisms and devices are so technically designed that they can interact with sub-cellular (i.e. molecular) levels of the body with a high degree of specificity. Thus therapeutic efficacy can be achieved to maximum with minimal side effects by means of the targeted cell or tissue-specific clinical intervention.

Nano drug delivery

Nano drug delivery is the application of nanotechnology in medicinal fields. Nano (symbol n) is derived from Greek meaning dwarf. One nanometer is, about 1/80,000 of the diameter of a human hair, or ten times the diameter of a hydrogen atom. 1 nanometer = 10- 9 or 0.000000001 meter = 0.000001 millimeter = 0.001 micrometer. Nanotechnology the science of the extremely small holds enormous potential for healthcare, from delivering drugs more effectively, diagnosing diseases more rapidly and sensitively, and delivering vaccines via aerosols and patches. It is the science of materials at the molecular or subatomic level. It involves manipulation of particles smaller than 100 nanometres
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(one nanometre is one-billionth of a metre) and the technology involves developing materials or devices within that size invisible to the human eye and often many hundred times thinner than the width of human hair. The physics and chemistry of materials are radically different when reduced to the nanoscale; they have different strengths, conductivity and reactivity, and exploiting this could revolutionise medicine.

Nanocarriers of drug delivery system

The integral components of drug delivery systems are usually the carriers in which the drug is embedded or covalently bound. The polymeric (or lipid) carriers will be able to transport the active agent to a specific desired target site (ligand, receptor, active site, etc.) to impart maximum therapeutic activity with maximum safety (i.e. protecting body tissues from adverse reactions while preventing the degradation/denaturation/ inactivation of the active agent during delivery/transit). Drugs are protected from interacting with other molecules which could cause a change in the chemical structure of the active ingredient causing it to lose its pharmaceutical action. Liposomes: Liposomes are spherical, artificial vesicles that comprise one or more lipid bilayer structures enclosing an aqueous core and are 50 nm to 1 m in size. The lipid bilayer helps to fuse with and penetrate membranes easily. Liposomes are high-potency carriers that protect encapsulated drugs from degradation. These can also be functionalized to improve cell targeting and solubility. These have been used to treat diseases such cancer, fungal infections, hepatitis A, and influenza. Nanospheres and nanocapsules: These are basically small vesicles used to transport materials. Nanospheres are typically solid polymers with drugs embedded in the polymer matrix.
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Nanocapsules are a shell with an inner space loaded with the drug of interest. Nanocapsules, existing in miniscule size, range from 10 nm to 1000 nm. They consist of a liquid/solid core in which the drug is placed into a cavity, which is surrounded by a distinctive polymer membrane made up of natural or synthetic polymers. Both systems are useful for controlling the release of a drug and/or protecting it from the surrounding environment. Both ensure that the drugs are released more slowly and steadily in the body Dendrimers: These are tree-shaped synthetic polymers with a controlled three-dimensional structure around a central core that carry drugs in the tips of the branches. Their typical size is 5 10 nm in diameter. Molecules can be entrapped in the space between the dendrimer's branches through ionic (acid/base), donoracceptor, Van der Waals and hydrogen-bonding interactions. Well-known dendrimers are created with poly(propyleneimine), poly(amidoamine), poly(Llysine), melamine, citric acid and poly(benzylether). The terminal groups can be modified to bind the drug and release it at a specific pH or upon encountering the appropriate enzyme. Micelles: A micelle (~10-100 nm) is a spherical conglomeration of amphiphilic molecules, such as cholesterol. In aqueous environments, the molecules form a tight ball with the hydrophobic groups on the inside and the hydrophilic groups on the outside. The reverse occurs in a nonaqueous environment. Micelles are useful for encapsulating non-water soluble drugs to be administered intravenously.

Figure: Schematic structure of different nanocarriers (liposomes, nanospheres, nanocapsules, dendrimers and micelles) for drug delivery. Buckyballs: These are spherical nanoparticles can carry more than one drug at a time. They are useful in the treatment of diseases such as cancer and other diseases where monotherapy can lead to drug resistance.

Figure: Showing how an antibody will only attach to a specific antigen that is the right shape and so buckyballs can be loaded with medicine (green) and attached to an antibody (pink) which will seek out the disease antigen. Nanobiomagnets: These carry drugs, for cancer for instance, into the body and are held at the target site by an external magnet. External magnetic fields can guide the delivery of their therapeutic load to specific areas of the body, minimizing toxicity and maximizing efficacy. The purpose of this is to concentrate the drug at the tumour site for long enough for it to be absorbed.

Recent discoveries
Table: Some selected US Food and Drug Administration-approved Nanopharmaceuticals Drug Product/ Brand Name Doxil, Caelyx Delivery Route Manufacturer / Alliance Indication(s) FDA Approval

IV

DaunoXome IV Abraxane IV

OrthoBiotech, ScheringPlough Gilead Sciences Abraxis BioScience, AstraZeneca

Metastatic ovarian cancer and AIDS-related Kaposis sarcoma Advanced HIV-related Kaposis sarcoma Various cancers

November 1995 April 1996 January 2005

AmBisome Myocet

IV IV

DepoCyt Amphotec

IV Subcutaneous

Gilead Sciences Zeneus Pharma, Sopherion Therapeutics SkyePharma, Enzon Sequus

Fungal infections

August 1997 cardio-protective formulation (Approved of doxorubicin used in late in Europe stage metastatic breast cancer and Canada) Lymphomatous meningitis April 1999 Invasive aspergillosis patients November who are refractory to or 1996 intolerant of conventional amphotericin B Leukaemia March 1990 Anaesthetic October 1989 Treatment of moderate to severe hot flushes in menopausal women Immunosuppress-ant for kidney transplants Lipid disorders; markedly reduces elevated plasma concentrations of triglycerides, LDL and total cholesterol & raises abnormally low levels of HDL Nausea in chemotherapy patients Chronic hepatitis C virus infection December 2006 September 1999 May 2005

Oncaspar Diprivan

Subcutaneous IV

Enzon Zeneca Pharmaceuticals BioSant

Elestrin

Transdermal

Rapamune Triglide

Oral solution Wyeth, Elan & oral tablet Oral tablets SkyePharma, First Horizon

Emend Pegasys

Oral capsule & IV Subcutaneous

Merck, Elan Nektar, Hoffmann-La Roche

March 2003 October 2002

Some applications of Nano drug delivery and their mechanisms

Therapeutic applications of nanotechnology are that it can provide new formulations of drugs with less side effects and routes for drug delivery. 1. Nano Drug Delivery in cancer treatment: Nanoparticles deliver chemotherapy drugs directly to cancer cells. Some mechanisms are discussed below-

i.

Many researchers attach ethylene glycol molecules to nanoparticles that deliver therapeutic drugs to cancer tumors. The ethylene glycol molecules stop white blood cells from recognizing the nanoparticles as foreign materials, allowing them to circulate in the blood stream long enough to attach to cancer tumors.

ii.

Using gold nanoparticles to deliver platinum to cancer tumors may reduce the side effects of platinum cancer therapy. The key is that the toxicity level of platinum depends upon the molecule it is bonded to. So the researchers chose a platinum containing molecule that has low toxicity to attach to the gold nanoparticles. When the platinum bearing nanoparticle reaches a cancer tumor it encounters an acidic solution which changes the platinum to its toxic state, in which it can kill cancer cells.

iii.

A method being developed to fight skin cancer uses gold nanoparticles to which RNA molecules are attached. The nanoparticles are in an ointment that is applied to the skin. The nanoparticles penetrate the skin and the RNA attaches to a cancer related gene, stopping the gene from generating proteins that are used in the growth of skin cancer tumors.

2. Nano Drug Delivery in Heart Disease: Some mechanisms for treating heart diseases are discussed belowI. Lab studies in mice have shown that using nanoparticles to target the delivery of the clot busting drug tPA (tissue plasminogen activator) can reduce the dosage of tPA needed, which may reduce possible side effects, such as internal bleeding. The clot busting drug was attached to a cluster of nanoparticles that break apart in regions of turbulent blood flow, like that found when a blood flow is restricted by a clot.

II.

Nanoparticles containing iron oxide that allows the nanoparticles to be directed, by a magnetic field, to stents. This could allow drugs to be delivered directly to stents placed in arteries.

3. Nano Drug Delivery in Diabetes: Researchers have developed nanoparticles that release insulin when glucose levels rise. The nanoparticles contain both insulin and an enzyme that dissolve in high levels of glucose. When the enzyme dissolves the insulin is released. In lab test these nanoparticles were able to control blood sugar levels for several days. It is still under investigation. 4. Nano Drug Delivery in Autoimmune diseases: A method has been developed to tackle autoimmune diseases uses nanoparticles to deliver antigens for a particular disease into the blood stream. The antigens reset the immune system, stopping white blood cells from attacking healthy cells. In the study, researchers attached myelin antigens to the nanoparticles and injected them intravenously into the mice. The particles entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. There, the particles were engulfed by macrophages, a type of immune cell, which then displayed the antigens on their cell surface. The immune system viewed the nanoparticles as ordinary dying blood cells and nothing to be concerned about. This created immune tolerance to the antigen by directly inhibiting the activity of myelin responsive T cells and by increasing the numbers of regulatory T cells which further calmed the autoimmune response. 5. Intranasal vaccine delivery: NanoBio's (a corporation involved in development and commercialization nanoemulsion technology) nanoemulsion-based, intranasal vaccines have elicited robust immune responses in animals vaccinated against influenza, RSV, urinary tract infection, pneumococcal disease, hepatitis B, RSV, anthrax, smallpox, cancer and other

diseases. In some cases, the immune response is exponentially higher than what is required to provide adequate protection against infection. The nanoemulsion is uniquely capable of permeating the nasal mucosa, where it loads vaccine antigen into immune-presenting cells. These cells then carry the antigen to areas of the body that initiate an immune response, including the lymph nodes, thymus and spleen producing both mucosal immunity and systemic immune response.

Figure: Mechanism of action of mucosal immunity and systemic immune response. 6. Antibody targeting of nanoparticles: Nanoparticles containing drugs are coated with targeting agents (e.g. conjugated antibodies). The nanoparticles circulate through the blood vessels and reach the target cells. Drugs are then released directly into the targeted cells, as shown in figure below.

Figure: Targeted drug delivery using a multicomponent nanoparticle containing therapeutic as well as biological surface modifying agents.

Advantages of nano drug delivery

The pathophysiological conditions and anatomical changes of diseased or inflamed tissues can potentially trigger a great deal of scopes for the development of various targeted nanotechnological products. This development is like to be advantageous in the following ways: 1. Drug targeting can be achieved by taking advantage of the distinct pathophysiological features of diseased tissues. 2. Various nanoproducts can be accumulated at higher concentrations than normal drugs. 3. Increased vascular permeability in tumors improves the effect of the nanosystems in the tumors or inflamed tissues through better transmission and retention.
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4. Nanosystems have capacity of selective localization in inflammed tissues. 5. Nanoparticles can be effectively used to deliver/transport relevant drugs to the brain overcoming the presence of bloodbrain barrier (meninges). 6. Drug loading onto nanoparticles modifies cell and tissue distribution and leads to a more selective delivery of biologically active compounds to enhance drug efficacy and reduces drug toxicity. 7. It involves low cost research compared that for discovery of new chemical entity. Minimizing the drug usage would significantly reduce the effective cost of drug which would give financial relief to the patients.

Nano drug technology in Bangladesh

Incepta Pharmaceuticals Ltd, a leading pharmaceutical company based in Dhaka, Bangladesh, has recently purchased Izon's qViro-X. The device utilize innovative nanopore-based detection and enables the study of a range of nano- and micro-scale particles, including viruses, exosomes and drug delivery particles, to characterize their samples with a level of detail not previously available. The detection mechanism is based on the idea that a virus particle, located inside of a nanopore, will increase the ionic resistance of the pore. If a constant voltage difference is applied across the pore membrane, this increase in resistance will cause a measurable decrease in current. This technique is not only rigorous but also sensitive to a single virus particle. qViro-X enables rapid and reliable counting of the total number of virus particles present in a sample ( viral particles / mL). It measures viral particle size on a particle-by-particle basis, providing accurate size distribution output, which is useful for assessment of viral aggregation
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and stability during vaccine production. The number of viral aggregates can be reliably measured and displayed in relation to the total number of pure virus particles in the sample. Currently the research team at Incepta is working on Rabies and Measles virus using this device. The R&D team at Incepta was attracted to Izon's qViro-X as it measures the individual particles which give accuracy in concentration, which is crucial in determining vaccine dosage as well as the minimal time that it takes to produce these accurate results. This technology, therefore, shows great promise in vaccine research.

Challenges of Nanotechnology for Drug Delivery

Biological Understanding: In order for bionanotechnologies to progress toward human applications, a better understanding of the mechanisms underlying intracellular uptake, trafficking and the fate of nanomaterials in complex biological networks is needed. Current delivery systems suffer from some major hindrances (e.g., rapid clearance by the immune system, low targeting efficiency and difficulty in crossing biological barriers). In view of these obstacles, a full understanding of the basic science of nanoparticle transport will result in achieving the ability to control and manipulate drug delivery. Safety Concern: Paralleling the development of nanomedicine, a field known as nanotoxicology has also emerged. Nanotoxicology refers to the study of the potential negative impact of the interactions between nanomaterials and biological systems. Some preliminary nanotoxicity investigations have led to the speculation that nanomaterials may contribute to the formation of free radicals, damage of brain cells and undesirable penetration through the epidermis or other physiological barriers into areas of the body that are more susceptible to toxic effects. NPs can be inhaled, ingested or absorbed through the skin, and they can penetrate cells, even into the cell

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nucleus, where, if sufficiently small, they can come into close contact with genetic material. Thus, nanomaterial toxicity should be considered relative to the patient population, as well as the entire manufacturing and disposal processes. Based on safety concerns, the establishment of standards or reference materials and consensus testing protocols that can provide benchmarks for the development of novel classes of materials are needed. Manufacturing Issue: Another challenge facing nanodrug delivery is the large-scale production of nanomaterials in terms of scaling up laboratory or pilot technologies for consistent and reproducible production and commercialization. A number of nanodrug delivery technologies may not be compatible with large-scale production owing to the nature of the preparation method and high cost of materials employed.

Figure: (A) At a laboratory scale, where good mixing could easily be attained & (B) at the industrial scale, where efficient stirring is difficult to achieve.
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The challenges of scaling up include a low concentration of nanomaterials, agglomeration and the chemistry process. It is much easier to modify or maintain the size or composition of nanomaterials at the laboratory scale for improved performance than at a large scale. Economic & Financial Barriers: Economic and financial barriers can also stand in the way of implementing nanomedicine. The limited availability of reimbursement by public and private health insurers for relatively expensive new diagnostic tests has emerged as a major impediment to the deployment of personalized medicine in general, and nanoproducts are likely to encounter even greater hurdles because of their costs and complexity. Despite the number of patents for nanodrug delivery technologies, commercialization is still in its early stage.

Conclusion
Nano drug delivery system, or in other words nanobiotechnology, is still in its early stages. Many diseases that do not have cures today may be cured by nanotechnology in the future. Since nanodrugs can easily penetrate the blood brain barrier researches are being undertaken to find a cure for diseases like brain cancer, Parkinsons diasease and Alzheimers disease using nanomedicine. Although the expectations from nanotechnology in medicine are high and the potential benefits are endlessly enlisted, the safety of nanomedicine is not yet fully defined. Use of nanotechnology in medical therapeutics needs adequate evaluation of its risk and safety factors. It is possible that nanomedicine in future would play a crucial/unparallel role in treatment of human diseases and also in enhancement of normal human physiology. If everything runs smoothly, nano drug delivery system will, one day, become an inevitable part of our everyday life and will help save many lives.

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